A Narrative Review of the Risk Factors for Cancer and the Preventive Opportunities: Current Status, Future Perspectives, and Implications for India

Tobacco

Intake of tobacco (both smoke and smokeless forms) accounts for 21% of total cancer deaths worldwide.¹ It increases the risk of lung cancer as well as 15 other cancers. Studies⁶ also demonstrate an increased risk following prolonged exposure to environmental tobacco smoke (second-hand aerosol from tobacco). Beedi smoking that is more prevalent in India is known to be more carcinogenic than the cigarettes. The benefits of tobacco cessation are applicable not just for cancer prevention but also for reducing the incidence of cardiovascular and pulmonary diseases. Its cessation depends on the interplay of sociocultural habits, personal awareness, and government legislation. Personal intervention may require behavioral counseling or pharmacotherapy or both. Evidence shows that those who initiate smoking at a young age tend to smoke for longer years, and the risk of lung cancer has a strong association with the duration of smoking than daily consumption.⁷

Passive smokers are exposed to both the mainstream and side stream smoke. During 2004, globally 40% of children, 33% of male nonsmokers, and 35% of female nonsmokers were exposed to second-hand smoke that resulted in 1% of worldwide mortality.⁷ The confounding effect of tea consumption along with smoking has been reported in Mu et al’s⁷ study. In this study, tea drinking was found to have protective effect with an adjusted odds ratio (OR) of 0.5 in nonsmokers and 0.45 in smokers. The 5 “A” method is useful for individuals who seek to quit (Ask, Advise, Assess, Assist and Arrange), and the 5 “R” method for those who are not yet willing to quit (Relevance of quitting, Risk of continuing tobacco, Rewards of quitting, Roadblocks to quitting and Repeat these at each visit). Subsequent to cessation of smoking, there is a significant residual risk of developing lung cancer.

Benzo(a)pyrene, a carcinogen found in cigarette smoke, is metabolically activated by the P450 family (CYP1A1) of hepatic enzymes. Such chemically active intermediate metabolites can bind to DNA and cause gene dysfunction. These products are detoxified by Glutathione-S-transferase, N-acetyl transferase, and epoxide hydrolase. Modified metabolic activity is a result of polymorphisms and/or gene deletions. Polymorphisms can also occur in enzymes responsible for DNA repair. Genetic alterations among these enzymes can have effects on the individual’s risk of developing lung cancer.⁸

Among smokers, relevant genetic abnormalities could be found among histologically normal bronchial epithelial cells. Thus, we could infer that a stepwise accumulation of genetic abnormalities leads to the development of cancer. Beyond the level of histological dysplasia, assessment of the accumulation of genetic alterations also provides information regarding the prognosis of lung cancer. The same could be done by fluorescence in situ hybridization, polymerase chain reaction-based loss of heterozygosity, comparative genomic hybridization, or sequence analysis.⁴ An early event in the development of squamous cell lung cancer (SCLC) includes SOX2 gene amplification (before other genetic changes) that is encoded on the chromosome 3q26.⁴ In some cases, specific epidermal growth factor receptor (EGFR), HER2 (human epidermal growth factor receptor 2), EML4-ALK (echinoderm microtubule associated protein like 4-anaplastic lymphoma kinase gene), or KRAS (Kirsten rat sarcoma viral oncogene homolog) mutations could precede the development of lung cancer.⁹

Spiral CT scanning provides a tool for early detection of lung cancer, as a complete image of the thorax can be obtained during a single hold of breath.¹⁰ This can locate considerably smaller cancers more frequently than with previous tools used for detection of lung cancer. Chest radiography is known to advance the diagnosis from clinical detection by ∼1 year.¹⁰ As computer-assisted diagnosis continues to evolve, it needs to be integrated into routine cancer screening and clinical management.

Alcohol

Alcohol consumption contributes to 4% of all cancers worldwide.¹ Alcohol is causally associated with cancers of the oropharynx and larynx, esophagus, breast, liver, and colon. For all these cancer sites, there is a dose–response relationship with no apparent threshold: the higher the average level of consumption, the higher the risk of cancer incidence.¹¹ The dynamics of alcohol consumption are complicated due to peer pressure and social cultures. It is identified as a chronic disease with genetic, psychosocial, and environmental factors. Ethanol (pure alcohol) is a procarcinogen found in all alcoholic beverages.¹¹ International Agency for Research on Cancer (IARC) labels procarcinogens as substances that transform into carcinogens by their metabolism.¹¹ World Cancer Research Fund/American Institute for Cancer Research recommends that for prevention of cancer, it is best to avoid consumption of alcohol.¹² We need to delineate how active alcohol use affects cancer treatment, the risk of recurrence, and overall prognosis, its interaction with oral chemotherapy and supportive care medications. Potential strategies to decrease the burden of cancer include initiatives for preventing consumption of alcohol.

The risk of cancer after alcohol cessation may be higher than that observed for current consumers of alcohol, because former drinkers might have been exposed to high doses of alcohol exposure. We need to design prospective studies that could longitudinally quantify the amount of alcohol consumed and the duration of cessation, which will characterize the impact of alcohol cessation on the risk of cancer. A synergistic interaction also exists between alcohol consumption and cigarette smoking, the biological underpinning of which may, however, not yet be explained. Genetic predisposition may amplify the toxic and mutagenic effects of alcohol consumption. Alcohol consumers with the inactive form of aldehyde dehydrogenase-2 experience excessive accumulation of acetaldehyde, which increases the susceptibility to alcohol induced cancer. Other mechanisms include oxidative stress, change in level of sex hormones, folate metabolism, DNA methylation, and cirrhosis leading to cancer.¹² Continuing the habit after cancer diagnosis could be associated with risk of its recurrence and/or secondary tumor.

Alcohol abuse induced comorbidities and subclinical factors such as nutritional deficiencies, immunosuppression, and cardiovascular insufficiencies could complicate the choice of treatment in cancer patients. We need to establish the impact of awareness initiatives on alcohol use in the community. Given the dose–response relationship between the level of alcohol use and cancer, policy initiatives should include population level measures such as higher taxation of alcoholic beverages, restrictions on availability, and ban on marketing.¹¹

Infections

Infections account for 20 to 25% of cancer cases worldwide¹ and are known etiological agents for cancers of stomach, cervix, and liver. Its prevalence is high in the developing Countries, due to the limited infection-prevention practices. Common infections include viruses such as human papilloma virus (HPV), hepatitis B and C virus (HBV and HCV), human T-cell lymphotropic virus (HTLV-1), human immunodeficiency virus (HIV), human herpes virus 8 and EBV. However, nonviral infections implicated in cancer causation include Helicobacter pylori (H. pylori) and some helminths (Clonorchis sinensis, Schistosoma haematobium).

HPV 16/18 has been detected in 80 to 85% of cervical cancers¹² however, few Indian women are identified to be at risk. HPV-16 is found in ∼90% of the HPV-positive oropharyngeal cancers (OPC). HPV-positive OPCs usually develop at a younger age and are less often associated with cigarette smoking than are the HPV-negative cancers.² India has 34 million carriers of HBV, and the risk of hepatocellular carcinoma in carriers of HBV and HCV is ∼1 to 3% over the course of 30 years.¹ HBV can integrate into the human genome and replicate within liver cells. This directly increases the carcinogenic activity in the liver through various signaling pathways. Unlike HBV, HCV is an RNA virus that cannot integrate into the human genome. Like HBV, HCV has a multifactorial role in the development of liver cancer including liver fibrosis, interaction with immune cells, affecting metabolic process, impacting apoptosis and cellular survival.

The Indian enigma is evident in the paradox of 50 to 80% prevalence of H. pylori infection that does not corroborate with the incidence of gastric cancer. This could be due to the mildly pathogenic variants of bacteria (NAB47 and NAD1) among the Indian population and other factors (dietary, tobacco, and socioeconomic status) that may mask the oncogenic effect of this infection. H. pylori infection causes chronic inflammation and theoretically fits the role of a promoter in the multistage model of carcinogenesis.¹³ It induces cell proliferation that in turn increases the risk for error in DNA replication and predisposes mucosal cells for transformation by dietary or endogenous mutagens.¹³ The likelihood of N-nitrosamine formation is enhanced as inflammatory cells increase the conversion of nitrates to nitrites. This possibly could be the reason for the epidemiologic observation in some population, where high dietary nitrates increase the risk of gastric cancer.¹³

Research into the etiology of sporadic colon cancer has focused on dietary influences. Trend analysis reveals that fats are consistent risk factors for colon cancer and fiber is consistently protective.¹³ Antibacterial strategies as in the case of H. pylori model are unlikely to play a role in the prevention of colon cancer. Many species of bacteria exist in the gut, and there is a possibility that specific bacterial species play direct role in colon carcinogenesis. However, as there is no specific organism that is the culprit of colon cancer, prevention strategies should focus on diet as it influences bacterial pathogenesis. The developing world also harbors parasites associated with human cancer such as Schistosomiasis for bladder cancer and liver flukes for cholangiocarcinoma (cancer of bile duct).

Globally, HPV is the most common sexually transmitted virus. During the period 1955 to 1992, there was a decline of ∼70% mortality due to cervical cancer among countries with preventive health services. Safe sexual practices could prevent majority of these infections (HPV, hepatitis and HIV). Universal guidelines for screening and transfusion of blood products and the disposal of needles/syringes will enable reducing the source of exposure. Vaccination strategies will address the risk of hepatitis and HPV infections.

Kaposi’s sarcoma is the most common cancer in untreated HIV-positive individuals. Kaposi sarcoma associated herpes virus is known as herpesvirus-8. HTLV-1 is a retroviral infection that affects the T-cells, but rarely causes adult T-cell leukemia (2–5% of infected individuals) or muscle disorders (0.25–2%). Although the cancer-causing mechanisms are poorly understood, T-cells infected by HTLV-1 can undergo genetic and epigenetic alterations. The Merkel cell polyoma virus causes a rare skin cancer “Merkel cell carcinoma” (MCC).

Endemic BL that occurs in the malaria belt is an EBV-positive malignancy that occurs several years after the primary infection with EBV.² BL is a monoclonal lymphoma of B-cell origin, wherein B-lymphocytes proliferate and there is a reduction in virus-specific cytotoxic T-cells due to the association with malaria. This results in an increase in the EBV viral load, enhancing the risk of chromosomal c-myc translocation, which is characteristic of BL.² EBV may serve as a polyclonal B-cell mitogen thus setting the stage for chromosomal mutations.

Fig. 1 depicts the list of risk factors associated with cancer, which are discussed in this article.

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Fig. 1 Risk factors associated with cancer.

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Air Pollution

Outdoor air pollution might cause cancer at sites other than lung through metabolism of the inhaled carcinogens. This includes breast, prostate, and colorectal regions. Household air pollution can happen from burning of solid fuels, passive smoking, and inadequate ventilation systems. Occupational exposure can happen from diesel and gasoline exhaust, polyaromatic hydrocarbons, inhalable dusts (metals, silica), work in mining, foundries, truck transportation, carbon black production, and with asphalt. The impact includes disruption of several molecular process through direct or indirect (inflammation and oxidative stress) damage, inducing tumor suppressor gene inactivation and the activation of oncogenes, cell cycle alterations-dependent on TP53 activation, activation of energetic dysregulation, chromosome instability, inhibition of apoptosis, and induction of cell proliferation in somatic cells.¹⁴

IARC considers diesel exhaust as a probable human carcinogen. Other carcinogenic airborne pollutants derived from motor vehicle exhaust include benzene, polyaromatic hydrocarbons, and persistent organic pollutants (dioxin). A critical component of air pollution includes the airborne PM, of different sizes from various sources and human activities. In the respiratory tract, PM can cause inflammation, free radical formation, oxidative DNA damage, cytotoxicity, and mutagenesis. Household pollutants are generated from combustion of coal as well as due to sulfur dioxide and oxides of nitrogen.

Combustion of fossil and biomass fuels releases air pollutants such as gaseous pollutants (sulfur dioxide, nitrogen dioxide, carbon monoxide, volatile organic compounds, and PM including carbonaceous aerosol particles). Submicron PM_2.5 is combustion related and of particular health concern as it contains numerous toxic compounds (acids and heavy metals), and tends to penetrate deeper into the lung than the larger PM generated by natural process such as soil particle mass.

A Chinese study¹⁵ found the risk among those burning solid fuel (coal, wood) to be four times more than those using clean energy. The usage of coal furnace for domestic heating carries twice the risk when compared with clean energy. Heatable brick bed exposure was associated with an eightfold increased risk. House layout and ventilation-related characteristics play important role in the risk of lung cancer. In the Indian context, since many females tend to work from within their homes and cook more frequently, the exposure at home has a stronger influence when compared with males.

It is imperative to monitor indoor exposure, regulate pollution levels and establish standard guidelines. It is a challenge to assess the exposure with regard to indoor air pollution. Using solid fuel for cooking and heating, and inadequate ventilation in the kitchen can significantly increase PM levels of all sizes during winter. Such association was not found during summers,¹⁵ as the ventilation-related characteristics of houses such as open windows enable reduction in levels of indoor air pollution.

Physical Inactivity

Physical inactivity, unhealthy diet, and obesity are associated with at least six cancers (colorectal, breast, stomach, liver, kidney, and endometrial).¹ Physical inactivity by itself is attributable to 5% of cancer deaths. The Japanese public health center prospective study reports a fewer incidence of carcinoma stomach, colon, liver, and pancreas among individuals with daily total physical activity (PA). Judicious exercise tends to reduce fatigue, anxiety and improves self-esteem, strength, and cardiovascular fitness. Among cancer patients, low intensity PA can reduce the risk of complications and disease progression. Yoga triggers neurohormonal mechanism by suppression of sympathetic activity and improving autonomic function along with reducing anxiety, stress, insomnia, fatigue, and mood disturbances. Yoga could be helpful in managing psychological stress, thereby improving physical healing as both are closely related.

PA is not just a means of preventing cancer but is also a therapeutic strategy for delaying relapse and extending life expectancy after diagnosis of cancer. The proposed hypothesis for the physiological mechanism of health benefits rendered by exercise-centered PA includes regulation of sex hormones, insulin, and insulin-like growth factor,⁷ regulation of immunological function, and inhibition of free radical production. The “Inverted J hypothesis” discusses this issue and also deliberates the immune-suppressive effect of sedentariness and repeated exhaustive exercise, which increase the susceptibility to cancer.¹⁶ Long-term regular exercise provides protection against diseases associated with chronic inflammation, by reducing the body fat component and release of catecholamines, inhibiting the production of proinflammatory cytokines and promoting the release of anti-inflammatory cytokines by the muscles.¹⁶ Individuals on low-calorie diet are physically active and tend to have low serum levels of inflammatory cytokines such as tumor necrosis factor-α, interleukin-6, and C-reactive protein.

Whether the nature of exercise is aerobic or anaerobic, natural killer (NK) cells are quickly mobilized to the peripheral circulation that in turn is linked to enhanced immune surveillance with transient increase in its cytotoxic activity.¹⁷ Evidence from studies suggests that mild physical exercise is safe and practicable during cancer therapy, and also improves quality of life during and posttreatment. We need to develop guidelines for planning the enhancement of PA and reducing sedentary behavior, together with details such as form, frequency, level, and duration of PA.

Diet

IARC reports on colon cancer indicate that a 17% increased risk exists for consumption of 100 g/day of red meat and 18% risk per 50 g/day of processed meat, and has identified them as potential carcinogens. The risk for cancer mortality was elevated with red meat (hazard ratio [HR]: 1.22, 95% confidence interval [CI]: 1.16–1.29) and processed meat (HR: 1.12, 95% CI: 1.06–1.19). However, the consumption of red and processed meat is <20% among the Indian population.¹

A major component of the Indian diet comprises of vegetarian diet (primarily cereals and pulses), which has been associated with a lower risk of cancer when compared with the primarily nonvegetarian diet of the Western population. Turmeric (curcumin) has been found to significantly suppress cancer induction by dietary benzopyrene in animal studies.¹

Among the Indian population, the following factors have been implicated in the causation of stomach cancer: spicy food, dried fish, and deep-fried cooking at high temperature (which generates polycyclic aromatic hydrocarbons). Many studies⁴ demonstrate the inverse correlation between the incidence of lung cancer and diets high in fruit and vegetables. However, this needs to be validated through interventional studies that assess the correlation between dietary manipulation and reduction in the incidence of lung cancer. The macro- and micronutrients that comprise our diet may act as cancer inhibiting substances. Studies have shown that foods rich in β-carotene and lycopene carotenoids have an inverse relationship with cancer of the bladder, lung, and prostate.⁸ Evidence also suggests that dietary flavonoids (found in apples) and isothiocyanates (found in cruciferous vegetables) have an inverse relationship with the incidence of lung cancer.⁸

Food is consumed as a part of the overall dietary pattern, wherein consumption includes a mixture of less healthful constituents as well as healthy dietary factors. There is clustering of lifestyle behaviors such as diet quality, PA, weight management, and smoking status. It is difficult to tease out the effect of a single element or behavior. The diet composition influences the microbiota of gut, which in turn affects the bioavailability of food components and metabolism of bioactive agents.¹⁸ In recent times, the importance of microbiome in health and disease has gained recognition.

Obesity: BMI (≥30 kg/m²)

It accounts for ∼8% (10% in men and 6% in women) of all cancers.¹ Singh et al¹⁹ report that among Indian women overweight (body mass index [BMI]: 25–29.9 kg/m²) and obesity (BMI: ≥30 kg/m²) have an OR of 1.06 and 2.27, respectively, as compared with normal weight women for developing breast cancer.

The pathogenic link between obesity and susceptibility to cancer includes proposed novel candidate mechanisms such as chronic inflammation, oxidative stress, synergism between tumor cells and surrounding adipocytes, migrating adipose stromal cells, obesity-induced hypoxia, shared genetic susceptibility, and the functional defeat of immune function.²⁰ The main systems identified in this association include insulin, insulin-like growth factor-1, sex steroids, and adipokines.²⁰ The worldwide rise in the incidence of obesity²⁰ has been associated with the change in morphology of esophageal cancer from squamous to adenocarcinoma (AC). The Framingham Heart study²⁰ shows that visceral adiposity, measured using multidetector computed tomography scan, is associated with cancer after adjustment for clinical risk factors and generalized adiposity. Certain conditions can foster particular tumors at specific sites due to the consequential effects of obesity, for example, heightened risk of cancer of the gall bladder when gall stones are present, and of esophageal AC as an effect of aggravated gastroesophageal reflux. Also, liver cancer can be a consequence of nonalcoholic steatohepatitis.²⁰

Supraphysiological concentrations of insulin are known to have mitogenic effects through its anabolic and antiapoptotic effects, as insulin in normal levels does not induce somatic cell mutations. In obesity, insulin is highly concentrated and cancer cells have the ability to respond to its activation effect via the intracellular transduction pathways.²⁰ Evidence suggests that energy accumulation leads to chronic inflammation in the body, and caloric restriction induces low inflammation.

Screening and Preventive Strategies

Available evidence suggests that during contemporary times, half of all cancers are preventable by practicing relevant measures. During the typical 10-minute encounter, the primary care physician should address the cancer-related risk factors and symptoms rather than focusing only on the patient’s complaints. Otherwise, this practice increases the risk of delayed presentation as the patient fails to communicate the full breadth and complexity of their symptoms. This in turn results in missed opportunities for early detection of cancers.

Goldie et al²¹ report the cost-effectiveness of cervical cancer screening in five developing countries including India using computer-based models. Screening women once in their lifetime at the age of 35 years (either by visual inspection of cervix with acetic acid or DNA testing for HPV in cervical cell samples) could reduce the lifetime risk by 25 to 36%, and would cost <500 USD per life year saved. Visual inspection for oral cancer screening by a trained health worker could lead to incremental (difference between intervention and control arms) cost per life year saved of USD 835 for all individuals and USD 156 for high-risk individuals.

Okonkwo et al²² report that mammographic screening and clinical breast examination (every 5 years or biennially) among Indian women are predicted to reduce breast cancer mortality by 8 and 16%, respectively. It is hypothesized that chest radiographic screening advances the diagnosis from clinical detection by ∼1 year.¹⁰

Chemoprevention

In chemoprevention, agents are used to prevent, inhibit, or reverse the process of carcinogenesis. The 5-year overall survival for lung cancer patients is only 16%⁴ and being the leading cause of cancer death in the world it makes an attractive case for chemoprevention. In SCLC and AC, the most common mutation is the loss of function of the p53 tumor-suppressor protein. However, restoring the function of p53 has not yet been translated therapeutically. Chemoprevention approaches will target processes such as interference with paracrine growth stimulation, suppression of inflammation, augmentation of apoptosis, improved immune surveillance, restoration of epithelial differentiation, and suppression of angiogenesis or invasion.⁴

Synthetic agents under investigation include nonsteroidal anti-inflammatory agents that are potent in vivo inhibitors of colon carcinogenesis, and difluoromethylornithine that is a polyamine synthase inhibitor known to have broad-spectrum in vitro and in vivo preventive activity. The role of the retinoid family as chemopreventive agent needs to be further investigated, with lung cancer being the prime target for these agents. The inverse relationship between the incidence of cancer and the selenium content of the soil (through locally grown foods) has been established.⁸ We need to gather evidence regarding whether supplementing the diet with these micronutrients is an effective method of cancer prevention.

Biomarkers of Carcinogenesis

Identification of novel cancer biomarkers is a challenge in cancer research, which could ideally be used as prognostic and diagnostic tools. Such biomarkers are present in tumor tissues or fluids, and include molecules such as DNA, mRNA, secreted proteins, transcription factors, cell surface receptors, and small metabolites.²³

Ex-smokers can have improvement in bronchial metaplasia or dysplasia, but the risk of cancer remains increased.⁸ Another molecular marker in lung cancer (apart from p53 tumor suppressor gene) includes inactivation of the p16 tumor suppressor gene from either mutation or allelic loss or hypermethylation of CpG islands in its promoter region. Cyclo-oxygenase (COX-2) is an alternative form of COX and is expressed in response to growth factors. The expression of COX-2 has been proposed to be an early marker of a genetically altered epithelial cell, which could potentially become a cancer. Many COX-2 inhibitors have inhibitory effects on cell lines.⁸ In some studies,⁸ sputum sample examination for molecular markers shows sites of DNA loss among smokers. These losses are localized to chromosomal sites important in cancer.

EGFR is expressed in the normal epithelium of cells, but their increased expression is found in metaplastic lesions. Among lung cancer cases, it is found in 70% of squamous cell carcinoma and ∼50% in AC. Specific agents such as celecoxib for blocking COX-2 enzyme and ZD1839 for inhibition of EGF activated tyrosine kinase are currently being used for treatment, and have the potential for being used as preventive agents.

Other novel biomarkers that could be used include transcriptomic signature derived from endobronchial or nasal brushings, biopsy, or serum proteomics and analysis of volatile organic compounds in the exhaled breath.⁴

An ingenious method of delivering the chemopreventive agent includes the inhalational route, as it maximizes drug delivery to the target organ and minimizes the systemic effects. Individuals with premalignant lesions that are characterized by activated PI3K signaling could be targeted by using myoinositol. Different interventions could target phenotypes such as airway or parenchymal inflammation, tissue hypoxia, incipient angiogenesis, or excessive expression of growth factor.⁴

Factors Which Prolong the Diagnosis of Lung Cancer

Lung cancer is different from other smoking-related diseases as even former smokers are at significant risk subsequent to smoking cessation. Some studies⁴ report a favorable response to chemoprevention among former smokers when compared with the current smokers. Globally, SCLC was the most common histological type of nonsquamous cell lung cancer (NSCLC) before the year 1975 and post-1975 there is a shift toward AC.⁹ The increase in incidence of AC has been attributed to a change in smoking pattern (filter cigarettes with low tar and high nitrate content), as well as due to nonsmoking-related factors.

A high proportion of Asian women who were never-smokers were diagnosed with lung cancer when compared with women in the United States (>65 vs. ∼10%).⁹ This could be due to the higher proportion of EGFR mutation in the Asian population. Such cancers among never-smokers are localized to the distal airways and favor the AC histology.⁹ Mu et al’s⁷ study indicates that exposures other than smoking are the causal factors for female lung cancers. When compared with clean energy, the coal furnace used as a means of domestic heating in rural areas is associated with twice the risk of lung cancer.⁷

Vashistha et al’s²⁴ study reports a delay of ∼100 days among Indian patients between developing symptoms and the definitive diagnosis. This duration extends by another 26 days for receiving the treatment. This confirms a study by Yurdakul et al² in Turkey, where the average time for receiving treatment after developing symptoms was 130 days. Redaneil et al² in their study at United Kingdom observed a median interval of ∼90 days after developing symptoms for subsequent diagnosis with lung cancer. Radzikowska et al² in their Polish study report a median duration of 90 days between onset of symptoms and administration of treatment. Also in Vashistha et al’s²⁴ study, chemotherapy was administered ∼2 to 3 weeks following confirmed diagnoses. This extension of time may be due to the design of a multidisciplinary treatment plan, which could be hastened through greater collaboration among the healthcare staff. Evans et al’s² study in Australia observed a 30-day delay in initiation of chemotherapy and Shao et al’s² study in china observed a 2-month delay. However, these patients had undergone an initial surgical or radiotherapy intervention unlike in Vashistha et al’s²⁴ cohort.

Vashistha et al²⁴ report patient and physician-level barriers for the mentioned time interval. At the patient level, barriers include lack of access to care and patients being ambivalent to their condition. Physician consultation involves out-of-pocket payment in India, and the level of poverty also contributes to the financial disadvantage. Physician-level delays are due to the differential tuberculosis (TB) diagnosis wherein the symptoms are mistaken to be similar. This is compounded by the initial radiographic signs that are quite similar. Data suggests that 25% of all new TB diagnosis is from India.⁵

Ramachandran et al²⁵ during the course of their study in South India report that <50% of physicians suspect lung cancer based on the presenting symptoms. The first differential diagnosis of TB was committed by ∼20% of the physicians. Physicians should exercise a high index of clinical suspicion among those at risk for lung cancer, and educate patients for accessing care at the onset of relevant symptoms.

Vashistha et al²⁴ report that ∼95% of patients with NSCLC present at their health center with either stage III or IV disease, while ∼75% with SCLC present with extensive stage disease. This can be compared with data from United States² that reports that <70% patients with NSCLC or SCLC are diagnosed with either regionally invasive or distant metastatic disease upon presentation.